tbuckley/cabot-search huggingface dataset:
Pomalidomide, bortezomib, and dexamethasone in lenalidomide-pretreated multiple myeloma: A subanalysis of OPTIMISMM by frailty.
Authors: Albert Oriol Rocafiguera, Meletios A. Dimopoulos, Fredrik Schjesvold, Meral Beksac, Münci Yagci, Alessandra Larocca, Shien Guo, Yutian Mu, Kevin Hong, Sujith Dhanasiri, Paul G. Richardson, Katja Weisel
Journal: Journal of Clinical Oncology (2022)

8024 Background: Patients (pts) with multiple myeloma (MM) are likely to be older adults, and advanced age is associated with lower survival rates, in part due to comorbidities and frailty. Results from the phase 3 OPTIMISMM trial (NCT01734928) demonstrated that pomalidomide (P) in combination with bortezomib + dexamethasone (Vd) significantly improved progression-free survival (PFS) in lenalidomide (LEN)-pretreated pts with relapsed/refractory MM (RRMM) vs Vd, irrespective of age and Eastern Cooperative Oncology Group performance status (ECOG PS). Here, we report results from a post hoc analysis assessing outcomes of PVd vs Vd in pts with RRMM by frailty status. Methods: Pts with MM and 1–3 prior lines of therapy (including a LEN-containing regimen) who had been randomized 1:1 to PVd or Vd were assessed for frailty. Frailty scores were calculated using age (≤ 75 yr = 0; 76–80 yr = 1; &gt; 80 yr = 2), the Charlson Comorbidity Index (≤ 1 = 0; &gt; 1 = 1) and ECOG PS (0 = 0; 1 = 1; ≥ 2 = 2). Pts were classified as non-frail (NF; combined score: 0 or 1) or frail (F; combined score: ≥ 2). PFS, overall response rate (ORR), and safety outcomes were assessed by treatment group and frailty status. Results: In the intent-to-treat population (N = 559) (data cutoff Oct 26, 2017), 93/281 (33.1%) pts who received PVd and 93/278 (33.5%) who received Vd were frail. Baseline characteristics were similar between treatment groups within each frailty subgroup. Median PFS was longer with PVd vs Vd in NF ( P = 0.001) and F ( P = 0.006) subgroups (Table). ORR was higher with PVd vs Vd in NF ( P &lt; 0.001) and F ( P &lt; 0.001) subgroups. Incidence of grade ≥ 3 (G3) treatment-emergent adverse events (TEAEs) was higher with PVd vs Vd in NF (88.1 vs 61.3%) and F (96.8 vs 87.9%) subgroups; peripheral neuropathy, acute renal failure, and hypertension were the most common. Treatment discontinuation due to G3 TEAEs was greater with PVd vs Vd in NF (19.2 vs 18.5%) and F (30.1 vs 20.9%) subgroups. PVd had a longer median treatment duration vs Vd in NF (8.8 vs 5.7 mo) and F (8.9 vs 4.3 mo) subgroups. Conclusions: Frail pts with RRMM who received PVd had longer PFS and higher ORR than pts who received Vd, consistent with the overall OPTIMISMM results. Frail pts experienced more G3 TEAEs and treatment discontinuations with PVd vs Vd, but treatment duration was longer with PVd vs Vd. Clinical trial information: NCT01734928. [Table: see text]
Prediction of pathological grading of high-risk solitary pulmonary nodules based on CT imaging deep learning: A multi-centric study.
Authors: Weihuan Lin, Weijie Zhan, HaiYu Zhou
Journal: Journal of Clinical Oncology (2022)

e13577 Background: Histopathological classification of operable early-stage lung adenocarcinoma may influence the intraoperative surgical decision and postoperative management for patients. However, it is difficult to comprehensively evaluate the grade of risk of operable lung adenocarcinoma based on preoperative CT imaging alone. Therefore, we aimed to establish a pathological grading model for patients with pulmonary nodules through preoperative CT imaging. Methods: This was a diagnostic, retrospective, multi-centric study conducted in two independent centers from January 1, 2019, to June 1, 2021. After inclusion and exclusion criteria, a total of 396 patients were included from two centers and were diagnosed as stage IA lung invasive adenocarcinoma (IAC). Patients (n=308) from the Guangdong Provincial People's Hospital with solitary pulmonary nodules were randomly divided into the training cohort (n=222) and the internal validation cohort (n=86). Patients from the Jiangxi Cancer Hospital comprised the external cohort (n=88). Their clinical characteristics and preoperative CT images were collected at the same high-quality standard. Extracted radiomic features from tumor and peritumor areas were selected via the least absolute shrinkage and selection operator (LASSO) algorithm for a radiomics model (RM) construction. Logistic Regression analysis was conducted to develop a novel multi-parameter model (MPM) that integrated clinical characteristics and radiomic features. The area under the curve (AUC) of the receiver operator characteristic curve (ROC) was calculated to compare the prediction performance of models. Results: The MPM composed of clinical characteristics and radiomic features performed better than RM. It achieved good predictive value for high-risk IAC. The AUC of MPM in the training cohort was 0.87 (95%CI, 0.81-0.92), which achieved better identification performance than the RM (See Table). Similarly, model comparisons were conducted in the two validation cohorts in which the MPM gained high AUC values of 0.78 (95%CI, 0.68-0.88) and 0.83 (95%CI, 0.74-0.91), respectively. In addition, the sensitivity of MPM was higher than 80.0% in the three cohorts. Conclusions: The MPM may be a practical and reliable tool for predicting the pathological risk of patients with solitary pulmonary nodules. [Table: see text]
Healthcare resource utilization (HCRU) and costs for patients (pts) with metastatic renal cell carcinoma (mRCC) receiving first-line (LOT1) pembrolizumab plus axitinib (P+A) or ipilimumab plus nivolumab (I+N).
Authors: Neil J. Shah, Reshma Shinde, Kristin Moore, Amy Sainski-Nguyen, Lisa Le, Feng Cao, Rui Song, Puneet Singhal, Robert J. Motzer
Journal: Journal of Clinical Oncology (2022)

4528 Background: Approval of immuno-oncology (IO) agents have changed treatment paradigm for mRCC pts. While IO-based therapies have demonstrated improved survival, these can be associated with considerable HCRU and costs necessitating their examination in real-world practice. Methods: This retrospective claims analyses utilizing Optum Research Database included adult pts with mRCC diagnosis from July-2017 to Aug-2020 and received P+A or I+N as LOT1 from Jan-2018 to May-2020 (first claim=index date). All eligible pts required continuous enrollment for minimum of 6-months prior and 3-months post the index date unless death occurred. All-cause HCRU counts, and associated costs were examined during the first 90 days (LOT1-90) and entire LOT1 duration and reported as overall and per-pt-per-month (PPPM) estimates. Results: The study identified 507 pts (P+A=126, I+N=381). Average age of the entire cohort was 67 years, 71% were male, mean NCI Charlson score was 2.4, and lung (55%) and bone (33%) were the most common metastatic sites. Mean (SD) distance from mRCC diagnosis to index date was 97 (172) days. Pts with P+A and I+N had similar baseline characteristics. Total % of pts with ambulatory visits was similar for P+A and I+N for LOT1-90 and entire LOT1 (99.2 vs. 100.0%, p=0.082 for both). During LOT1-90, we observed a lower % of pts on P+A with ER visits and inpatient (IP) stay compared to I+N (34 vs. 48, p=0.008; 19 vs. 38, p&lt;0.001, respectively). We also observed a shorter mean (SD) IP stay for P+A vs. I+N during LOT1-90 (1.9 (6.5) vs. 5.6 (13.24) days, p&lt;0.001). Similarly, P+A had lower mean PPPM ambulatory visits, IP stay, and ICU stay during both LOT1-90 and entire LOT1 (Table). In addition, mean PPPM total (medical + pharmacy) and mean PPPM medical costs were lower for P+A compared to I+N, but mean PPPM pharmacy costs were higher for P+A for both LOT1-90 and entire LOT-1 (Table). Conclusions: This study noted significantly higher HCRU with I+N including higher mean PPPM ambulatory visits, IP stays, and ICU stays compared to P+A. Although, P+A had higher mean PPPM pharmacy costs, the total medical plus pharmacy costs were significantly lower compared to I+N. [Table: see text]
Genomic and immunological characterization between primary and recurrent breast cancer.
Authors: Danni Liu, Jing Zhang, Suo Peisu, Shifu Chen, Xiufan Peng
Journal: Journal of Clinical Oncology (2022)

e12553 Background: A large number of breast cancer patients suffered cancer recurrence. Survival was seriously worse in recurred tumor. Immune microenvironment and pathways inducing drug resistance were closely related to tumor recurrence. It is necessary to clarify the recurrence mechanisms and improve recurrence detection. Methods: Somatic mutation, expression matrix and clinical information of primary (n = 1177) and recurred (n = 803) breast tumors in METABRIC were downloaded from cBioPortal. The Kaplan-Meier method of survival analysis was used to display overall survival. Significantly mutated genes (SMG) identified by MutSig2CV (v3.11) with Qvalue &lt; 0.05. R packages CIBERSORT was applied to calculate the proportion of tumor-infiltrating immune cell using mRNA expression microarray data. Student's t-test was used to compare the SMGs expression log intensity levels of two groups. Results: Overall survival were significantly difference between the primary and recurred patients (log-rank test, P value &lt; 0.0001). The immune cell components of primary and recurred breast tumors presented different patterns. Macrophages were significantly enriched in primary patients (Kruskal-Wallis test, P value &lt; 0.05). PIK3R1, SMAD4, ATR and FLT3 were uniquely significantly mutated and expressed at lower levels in recurred group. These SMGs were identified as being associated with recurrence in other cancer studies. For example, PIK3R1 regulates the transduction of PI3K/Akt pathway, which disrupting the balance between induction and prevention of apoptosis, causing drug resistance. In the other, SMAD4 acts as a central mediator of TGF-β/SMAD4 signaling pathway that usually impedes immune cell activation. Conclusions: Recurred breast tumors presented different genetic mutation frequency and microenvironment. Tumor immune factors are associated with recurrence. Detecting uniquely SMGs of recurred breast tumors may be a feasibility way to monitor disease recurrence.
An open-label, multicenter, phase 1 study of RP3 as a single agent and in combination with nivolumab in patients (pts) with solid tumors.
Authors: Kevin Joseph Harrington, Antonio Rullan, Louise Deighton, Joao Barata, Henry Castro, Christoph Matthias Ahlers, John McRae, Praveen Bommareddy, Robert S. Coffin, Mark R. Middleton
Journal: Journal of Clinical Oncology (2022)

TPS2705 Background: RP3 is a genetically modified herpes simplex virus 1 (HSV-1) that contains insertions for the gibbon ape leukemia virus surface glycoprotein (GALV-GP) with the R- sequence deleted (R-), an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule, CD40 ligand, and 4-1BB ligand. Together, these insertions are expected to increase oncolytic potency, cell-to-cell spread, immunogenic cell death, and systemic immune activation. RP3 has demonstrated antitumor activity in preclinical models using viruses similar to RP3 expressing murine versions of anti-CTLA-4, CD40L, and 4-1BBL both alone and in combination with PD1-1 blockade. Methods: This is an open-label, multicenter, Phase 1 study evaluating RP3 as monotherapy or in combination with nivolumab (nivo) in patients (pts) with solid tumors (NCT04735978). Part 1 evaluated escalating doses of RP3. Pts in Part 1 received IT injections of up to 10 mL RP3 into superficial, nodal, or visceral lesions Q2W x 5 across two dose levels (DL1: 10 5 plaque-forming units (PFU)/mL once, then 10 6 PFU/mL x 4; DL2: 10 6 PFU/mL once, then 10 7 PFU/mL x4). The RP2D is 10 6 PFU/mL once, followed by 10 7 PFU/mL IT Q2W. In Part 2, pts are being enrolled into expansion cohorts of 45 patients with GI (including HCC), lung, breast, and squamous cell carcinoma of the head and neck treated with RP1 combined with nivo. Additional cohorts will enroll patients treated with RP3 followed by nivo, RP3 monotherapy to further explore biomarkers in injected and uninjected tumors, and with the potential to also open a cohort in melanoma. Pts in both Part 1 and Part 2 may receive up to 8 additional doses of RP3 if protocol-specified criteria are met. Key inclusion criteria: confirmed advanced or metastatic non-neurological solid tumors, at least one measurable tumor ≥ 1 cm and injectable tumors ≥ 1 cm in aggregate, ECOG ≤1, and adequate hematologic, hepatic, and renal function. In Cohorts 1, 2, and 4, approximately 50% of the pts with lung, breast, and GI cancer must have liver lesions intended for injection. Exclusion criteria include prior oncolytic virus treatment, need for immunosuppressive therapy, an autoimmune disease requiring systemic therapy, active significant herpetic infections or prior complications of HSV-1 infection, active or chronic HBV or HCV infection, known HIV infection, or prior active malignancy within 3 years. Clinical trial information: NCT04735978.
Diagnostic signature of circulating miRNAs in glial brain tumors.
Authors: Anton A. Pushkin, Eduard E. Rostorguev, Sergey E. Kavitskiy, Elena A. Dzhenkova, Oleg I. Kit, Marina A. Engibaryan, Vladimir N. Kasyanenko
Journal: Journal of Clinical Oncology (2022)

e14027 Background: Circulating microRNAs (miRNAs) are currently being investigated as non-invasive diagnostic biomarkers in a wide range of tumors. However, there is still no sufficiently reliable siRNA signature for routine screening of patients with glial tumors of varying degrees of malignancy. Our study aimed to determine the level of microRNA pattern in the blood plasma of patients with glial tumors, which previously showed aberrant expression in tumors. Methods: Relative expression of twenty miRNAs (hsa-miR-3180, hsa-miR-3180-3p, hsa-miR-6782-5p, hsa-miR-182-5p, hsa-miR-133b, hsa-miR-670-3p, hsa-miR-342-3p, hsa-miR-454-3p, hsa-miR-1246, hsa-miR-433-3p, hsa-miR-195-5p, hsa-miR-29a-3p, hsa-miR -107, hsa-miR-21, hsa-miR-122, hsa-let-7c-5p, hsa-miR-125b-5p, hsa-miR-190b, hsa-miR-196a-3p, hsa-miR-16 -5p) was studied in the blood plasma of patients with glial tumors of various grades of malignancy (diffuse astrocytoma (DA, n=10), anaplastic astrocytoma (AA, n=10) and glioblastoma (GB, n=10)) and patients with menigioma (MEN, n=10) compared with a conditionally healthy group (CNTRL, n=10) by RT-PCR. Cycle thresholds were normalized to exogenous cel-miR-39-5p. Relative expression (RE) was calculated using the 2 ΔΔ Ct method. Wilcoxon's t-test and Benjamini-Hochberg multiple comparison adjustment were used to assess differences. Results: As a result of evaluating the relative expression of the studied miRNAs between groups, differences were found for 9 miRNAs. P-values are listed in the Table. Conclusions: Thus, circulating miRNAs could potentially act as biomarkers for both gliomas and their subtypes and differentiate gliomas from meningiomas. The findings may provide new diagnostic strategies for gliomas. Significance levels of differences in the relative expression of miRNAs when comparing the studied groups with each other.[Table: see text]
Phase 1 trial of first-line bintrafusp alfa in combination with other anticancer therapies in patients (pts) with locally advanced or advanced cervical cancer.
Authors: Ana Oaknin, Sharad A. Ghamande, Yuka Kasamatsu, Marta Gil-Martin, Elisabeth J. Diver, Genevieve Jehl, Stephan A. Gleicher, Surendra Chaudhary, Yulia Vugmeyster, Kosei Hasegawa
Journal: Journal of Clinical Oncology (2022)

5528 Background: Until the recent FDA approval of pembrolizumab in combination with chemotherapy ± bevacizumab, there have been limited treatment options that address the underlying biology for pts with persistent, recurrent, or metastatic (P/R/M) or locally advanced (LA) cervical cancer. Persistent HPV infection is associated with 99% of cervical cancers and is linked to upregulation of TGF-β. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1, has shown promising clinical activity and manageable safety in pts with recurrent or metastatic cervical cancer. We report data from a phase 1 trial evaluating safety of first-line bintrafusp alfa plus chemotherapy ± bevacizumab for pts with P/R/M cervical cancer or bintrafusp alfa plus chemoradiotherapy for pts with LA cervical cancer (INTR@PID 046; NCT04551950). Methods: Pts with P/R/M cervical cancer who had not received prior systemic therapy received bintrafusp alfa 2400 mg Q3W plus cisplatin/carboplatin and paclitaxel with (cohort 1A) or without (cohort 1B) bevacizumab. Pts with LA cervical cancer received bintrafusp alfa 2400 mg Q3W plus concurrent weekly cisplatin and radiotherapy followed by maintenance therapy with bintrafusp alfa (cohort 2). Pts were treated until disease progression, death, unacceptable toxicity, or withdrawal. Primary endpoints were safety and tolerability of bintrafusp alfa in combination with current standard-of-care therapies in pts with P/R/M or LA cervical cancer. Results: As of November 25, 2021, 8 pts in cohort 1A, 9 in cohort 1B, and 8 in cohort 2 had received bintrafusp alfa for a median of 11.6, 10.0, and 5.6 cycles, respectively. At the time of this analysis, 11 of 25 pts remained on bintrafusp alfa therapy. Any-grade bintrafusp alfa–related adverse events (AEs) occurred in 75.0%, 100.0%, and 75.0% of pts in cohorts 1A, 1B, and 2, respectively (Table). The most-common grade ≥3 AEs were anemia and hematuria (25.0% each) in cohort 1A and vaginal hemorrhage (22.2%) in cohort 1B. One pt had grade 4 anemia and vaginal hemorrhage in cohort 1B. No treatment-related deaths occurred. AEs led to permanent discontinuation of bintrafusp alfa in 37.5%, 33.3%, and 12.5% of pts in cohorts 1A, 1B, and 2, respectively; the most common any-grade AE was vaginal hemorrhage (22.2%). Conclusions: No new safety signals were observed with first-line bintrafusp alfa plus chemotherapy ± bevacizumab or chemoradiotherapy in pts with P/R/M or LA cervical cancer. Clinical trial information: NCT04551950. [Table: see text]
Increased lung metastasis with sevoflurane in breast cancer surgery is associated with VEGF and elevated vascular permeability by VEGF in a mouse model of human breast cancer.
Authors: Jun Lin, Ru Li, Yujie Huang, James P. Dilger, Mousumi Beto Mukherjee
Journal: Journal of Clinical Oncology (2022)

e13060 Background: An on-going controversy is whether general anesthetics used in cancer surgery substantially influence the outcome of cancer patients. Thousands of cancer patients undergo surgery with hope of cure. However, postoperative metastasis remains a deadly disease that affects millions of lives, even with all the recent therapeutic advancements. Anesthesia is required for surgical resection of solid tumors and we have shown that general anesthetics substantially influences the process of breast cancer lung metastasis through increasing pulmonary permeability in animal models. Our previous study demonstrates that inhaled anesthetic sevoflurane used during resecting primary breast tumors promotes lung metastasis via IL6 pathway in syngeneic model of murine 4T1 breast cancer cells, compared with an intravenous anesthetic propofol. Methods: Xenograft model of human MDA-MB 231 breast cancer of spontaneous metastasis was utilized in this study to evaluate the effect of commonly used general anesthetics including sevoflurane and propofol on breast cancer lung metastasis and explore the potential mechanism. Results: In this study we show that the metastatic promoting effect of sevoflurane is associated with elevated secretion of VEGF and increased vascular permeability in xenograft model of human MDA-MB 231 breast cancer of spontaneous metastasis. Cytokine array profiling reveals that the mice receiving sevoflurane have increased levels of pro-angiogenic factor VEGF in serum and lung tissues. Sevoflurane enhances the expression level of VEGFR on HUVEC cells. Furthermore, sevoflurane disrupts endothelial monolayer in vitro and elevates pulmonary vascular permeability in vivo. The sevoflurane-promoted breast cancer lung metastasis is reversed by DC101, an antibody targeting mouse VEGFR-2. Conclusions: Our results show that the inhaled anesthetic sevoflurane during surgical removal of primary tumor alter the course of metastasis through regulating secretion of VEGF and associated vascular remodeling. The mechanistic study of general anesthetics on cancer cell metastasis establishes the causal link and could provide the potential therapeutic intervention and guide the clinical trials.
Platinum vs non-platinum chemotherapy for platinum-resistant ovarian cancer: A meta-analysis.
Authors: Alexey Rumyantsev, Alexandra Tyulyandina, Mikhail Fedyanin, Ilya Pokataev, Elena Glazkova, Edgar Israelyan, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2022)

e17551 Background: recurrent ovarian cancer (OC) patients with platinum-free interval (PFI) &lt; 6 mo. are usually considered platinum-resistant and treated with non-platinum chemotherapy. However, this practice is not based on proper-conducted randomized trials. Methods: we queried the PubMed database for all full-text articles and abstracts on the treatment of patients with platinum-resistant ovarian cancer (PROC) in 01/01/2000-01/06/2019 timeframe. The PRISMA tool was used to ensure transparent reporting of the results. Inclusion criteria were: 1) histologically confirmed epithelial OC; 2) recurrent disease within 6 months after completion of platinum chemotherapy; 3) treatment with platinum- or non-platinum chemotherapy agents that are routinely used for OC; 4) no concomitant therapy with targeted or investigational agents; 5) defined response rate (RR) and assessment criteria. Proportion meta-analysis (random-effect model) and beta-regression were conducted to assess the impact of platinum agents on response rate as well as significance of other variables. In the beta-regression model response rate was a dependent variable, while platinum agents (yes or no), used non-platinum drugs and method of response assessment were independent variables. Statistical analysis was dose with meta and betareg packages of R software. Results: we identified 7156 articles and screened them for title and abstract, 157 studies for further analysis. Efficacy of non-platinum- and platinum-based therapy was assessed in 113 (n = 5272) and 44 (n = 1055) trials respectively. In meta-proportion random-effect model RR among patients treated with platinum-based and non-platinum chemotherapy RR was 36% (95% CI 30-41; I 2 = 62%) and 16% (95% CI 14-19; I 2 = 70%) respectively. Multiple beta-regression model is presented in the Table below. For sensitivity analysis various regression models were made with different subsets of the trials and additional variables (including year of the trial, percentage of serous subtype of OC and median of prior therapy lines). Platinum was the strongest predictor of response in every developed model. Conclusions: this meta-analysis shows that patients with 'platinum-resistant' ovarian carcinoma may derive significant benefit from reintroduction of platinum agents. These results support recent ESMO-ESGO consensus on treatment of recurrent ovarian cancer and randomize trials are required to refine the role of platinum in early relapsed OC.[Table: see text]